Clinical Associations of the Risk Alleles of HLA-Cw6 and CCHCR1*WWCC in Psoriasis

Kainu, Kati; Onkamo, Päivi; Tiala, Inkeri; Himberg, Johan; Koskinen, Lotta; Snellman, Erna; Karvonen, Seija-Liisa; Karvonen, Jaakko; Uurasmaa, Tutta; Reunala, Timo; Kivikäs, Kristiina; Jansén, Christer T.; Holopainen, Päivi; Elomaa, Outi; Kere, Juha; Saarialho–Kere, Ulpu

doi:10.2340/00015555-0184

Cited by 21 publications

(22 citation statements)

References 37 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CCHCR1 is a regulator of keratinocyte proliferation or differentiation and is overexpressed in keratinocytes in psoriatic lesions. [20][21][22][23] TCF19 is a potential trans-activating factor that could play an important role in the transcription of genes required for the later stages of cell cycle progression. 27 Possible psoriasis candidate genes near HLA-B include PSORS1C1, [17][18][19] CCHCR1, 22,23 and POU5F1.…”

Section: Discussionmentioning

confidence: 99%

A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients

et al. 2011

View full text Add to dashboard Cite

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

show abstract

Section: Discussionmentioning

confidence: 99%

A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients

et al. 2011

View full text Add to dashboard Cite

show abstract

“…This is expected because two SNPs are in strong LD (r2 = 0.935, D′ = 0.998) and both are good approximate to HLA-C *0602, known to be associated with psoriasis. SNP rs1265181 in HCG27 is the top association signals in a GWAS of psoriasis in Han Chinese population [11], while rs130065 in CCHCR1 has been consistently associated with psoriasis in multiple populations [25], [26], [27], and HCR1 protein expressed differently between lesional skin and normal skin [26]. CCHCR1 may function as a negative regulator of keratinocyte proliferation; aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis [28].…”

Section: Discussionmentioning

confidence: 99%

Psoriasis Regression Analysis of MHC Loci Identifies Shared Genetic Variants with Vitiligo

Zhu

Xian

et al. 2011

PLoS ONE

View full text Add to dashboard Cite

Psoriasis is a common inflammatory skin disease with genetic components of both immune system and the epidermis. PSOR1 locus (6q21) has been strongly associated with psoriasis; however, it is difficult to identify additional independent association due to strong linkage disequilibrium in the MHC region. We performed stepwise regression analyses of more than 3,000 SNPs in the MHC region genotyped using Human 610-Quad (Illumina) in 1,139 cases with psoriasis and 1,132 controls of Han Chinese population to search for additional independent association. With four regression models obtained, two SNPs rs9468925 in HLA-C/HLA-B and rs2858881 in HLA-DQA2 were repeatedly selected in all models, suggesting that multiple loci outside PSOR1 locus were associated with psoriasis. More importantly we find that rs9468925 in HLA-C/HLA-B is associated with both psoriasis and vitiligo, providing first important evidence that two major skin diseases share a common genetic locus in the MHC, and a basis for elucidating the molecular mechanism of skin disorders.

show abstract

“…The Swedish and Finnish psoriasis family material for genotyping was recruited as previously described: the Swedish blood samples were collected with the help of the Swedish Psoriasis Association and approved by the Regional Ethics Committee [67], the Finnish samples were approved by the Ethics Committees of Helsinki, Turku, Tampere, and Oulu University Central Hospitals and Central Hospital of Päijät-Häme [68], [69]. The skin samples for expression studies were dermatome biopsies measuring 5×2 cm, 4–6/1000 inches thick (Zimmer® dermatome, Minneapolis, MN).…”

Section: Methodsmentioning

confidence: 99%

Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization

et al. 2012

View full text Add to dashboard Cite

CCHCR1 (Coiled-Coil α-Helical Rod protein 1), within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5′-region of the gene contains a SNP (rs3130453) that controls a 5′-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10−7). Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.

show abstract

Clinical Associations of the Risk Alleles of HLA-Cw6 and CCHCR1*WWCC in Psoriasis

Cited by 21 publications

References 37 publications

A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients

A whole-genome association study of major determinants for allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis in Japanese patients

Psoriasis Regression Analysis of MHC Loci Identifies Shared Genetic Variants with Vitiligo

Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization

Contact Info

Product

Resources

About